1uhl
From Proteopedia
(New page: 200px<br /> <applet load="1uhl" size="450" color="white" frame="true" align="right" spinBox="true" caption="1uhl, resolution 2.90Å" /> '''Crystal structure o...) |
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| - | [[Image:1uhl.gif|left|200px]]<br /> | + | [[Image:1uhl.gif|left|200px]]<br /><applet load="1uhl" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1uhl" size=" | + | |
caption="1uhl, resolution 2.90Å" /> | caption="1uhl, resolution 2.90Å" /> | ||
'''Crystal structure of the LXRalfa-RXRbeta LBD heterodimer'''<br /> | '''Crystal structure of the LXRalfa-RXRbeta LBD heterodimer'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The nuclear receptor heterodimers of liver X receptor (LXR) and retinoid X | + | The nuclear receptor heterodimers of liver X receptor (LXR) and retinoid X receptor (RXR) are key transcriptional regulators of genes involved in lipid homeostasis and inflammation. We report the crystal structure of the ligand-binding domains (LBDs) of LXRalpha and RXRbeta complexed to the synthetic LXR agonist T-0901317 and the RXR agonist methoprene acid (Protein Data Base entry 1UHL). Both LBDs are in agonist conformation with GRIP-1 peptides bound at the coactivator binding sites. T-0901317 occupies the center of the LXR ligand-binding pocket and its hydroxyl head group interacts with H421 and W443, residues identified by mutational analysis as critical for ligand-induced transcriptional activation by T-0901317 and various endogenous oxysterols. The topography of the pocket suggests a common anchoring of these oxysterols via their 22-, 24- or 27-hydroxyl group to H421 and W443. Polyunsaturated fatty acids act as LXR antagonists and an E267A mutation was found to enhance their transcriptional inhibition. The present structure provides a powerful tool for the design of novel modulators that can be used to characterize further the physiological functions of the LXR-RXR heterodimer. |
==About this Structure== | ==About this Structure== | ||
| - | 1UHL is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with 444 and MEI as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1UHL is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=444:'>444</scene> and <scene name='pdbligand=MEI:'>MEI</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1UHL OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Jacobsson, M.]] | [[Category: Jacobsson, M.]] | ||
[[Category: Jendeberg, L.]] | [[Category: Jendeberg, L.]] | ||
| - | [[Category: Johansson, I | + | [[Category: Johansson, I C.]] |
[[Category: Norstrom, C.]] | [[Category: Norstrom, C.]] | ||
[[Category: Ogg, D.]] | [[Category: Ogg, D.]] | ||
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[[Category: ligand-binding domain]] | [[Category: ligand-binding domain]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:24:34 2008'' |
Revision as of 13:24, 21 February 2008
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Crystal structure of the LXRalfa-RXRbeta LBD heterodimer
Overview
The nuclear receptor heterodimers of liver X receptor (LXR) and retinoid X receptor (RXR) are key transcriptional regulators of genes involved in lipid homeostasis and inflammation. We report the crystal structure of the ligand-binding domains (LBDs) of LXRalpha and RXRbeta complexed to the synthetic LXR agonist T-0901317 and the RXR agonist methoprene acid (Protein Data Base entry 1UHL). Both LBDs are in agonist conformation with GRIP-1 peptides bound at the coactivator binding sites. T-0901317 occupies the center of the LXR ligand-binding pocket and its hydroxyl head group interacts with H421 and W443, residues identified by mutational analysis as critical for ligand-induced transcriptional activation by T-0901317 and various endogenous oxysterols. The topography of the pocket suggests a common anchoring of these oxysterols via their 22-, 24- or 27-hydroxyl group to H421 and W443. Polyunsaturated fatty acids act as LXR antagonists and an E267A mutation was found to enhance their transcriptional inhibition. The present structure provides a powerful tool for the design of novel modulators that can be used to characterize further the physiological functions of the LXR-RXR heterodimer.
About this Structure
1UHL is a Protein complex structure of sequences from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
Reference
Crystal structure of the heterodimeric complex of LXRalpha and RXRbeta ligand-binding domains in a fully agonistic conformation., Svensson S, Ostberg T, Jacobsson M, Norstrom C, Stefansson K, Hallen D, Johansson IC, Zachrisson K, Ogg D, Jendeberg L, EMBO J. 2003 Sep 15;22(18):4625-33. PMID:12970175
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